The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity.
The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity.
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DOI：
10.4049/jimmunol.1402070
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发表时间：
2015-01-15
期刊：
影响因子：
--
通讯作者：
Meinl E
中科院分区：
文献类型：
--
作者：
Hoffmann FS;Kuhn PH;Laurent SA;Hauck SM;Berer K;Wendlinger SA;Krumbholz M;Khademi M;Olsson T;Dreyling M;Pfister HW;Alexander T;Hiepe F;Kümpfel T;Crawford HC;Wekerle H;Hohlfeld R;Lichtenthaler SF;Meinl E
BAFF and APRIL, which control B-cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL-receptor TACI, was applied in clinical trials. However disease activity in multiple sclerosis (MS) unexpectedly increased, whereas in systemic lupus erythematosus (SLE) atacicept was beneficial. Here, we show that an endogenous soluble form of TACI exists in vivo. TACI proteolysis involved shedding by ADAM10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand-independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B-cell survival and NFκB-activation. We determined sTACI levels in autoimmune diseases with established hyper-activation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid (CSF) of the brain-restricted autoimmune disease MS correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease SLE correlating with disease activity. Together, we show that TACI is sequentially processed by ADAM10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. Itreflectssystemic and compartmentalized B-cell accumulation and activation.
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DOI：
10.1084/jem.20091990
发表时间：
2010-03-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gibb DR;El Shikh M;Kang DJ;Rowe WJ;El Sayed R;Cichy J;Yagita H;Tew JG;Dempsey PJ;Crawford HC;Conrad DH
通讯作者：
Conrad DH
BAFF由星形胶质细胞产生，并在多发性硬化病变和原发性中枢神经系统淋巴瘤中上调。
影响因子：
15.3
作者：
Krumbholz, M;Theil, D;Derfuss, T;Rosenwald, A;Schrader, F;Monoranu, CM;Kalled, SL;Hess, DM;Serafini, B;Aloisi, F;Wekerle, H;Hohlfeld, R;Meinl, E
通讯作者：
Meinl, E
影响因子：
30.8
作者：
Castigli, E;Wilson, SA;Geha, RS
通讯作者：
Geha, RS
影响因子：
32.4
作者：
Figgett, William A.;Fairfax, Kirsten;Mackay, Fabienne
通讯作者：
Mackay, Fabienne
影响因子：
4.8
作者：
Reddy, P;Slack, JL;Black, RA
通讯作者：
Black, RA